Heparinization of plastic

ABSTRACT

Plastics are rendered nonthrombogenic by heparinizing them following a treatment with an amino alkyl tri alkoxy silane in an inert solvent. The solvent is preferably one capable of swelling the plastic. In the treatment of fluorocarbon plastics, a preliminary treatment with sodium is employed. The amino groups which become attached to the plastic are thus caused to bond heparin to the surface effectively to impart anticoagulating properties.

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[54] HEPAIRHWHZATIGN UF PLASTMC V 7 OTHER PUBLICATIONS [72] Inventor;Manfred H Dych, North Miami, Fla, Falb et al., Development of BloodCompatible Polymeric Materials," Battelle Memorial Institute, Columbus,Ohio, 1731 Assrgnee. Curdis Corporation, Miami, Fla. June 22 1966,)? 18.l22l Filed: fiept. 16, 1968 Union Carbide, Organofunctional Silanes,"1956, pp. 14-

16. [21 I Appl. No.: 762,376

Primary Examiner-William D. Martin [52] 111.8. 1C1 ..l117/4i7 A,117/138.8 UF, 117/161 ZA, As$iSla"tEXl/1mi"er-D- Cohen 424/133, 3/ 1Attarney-Kenway, Jenney & l-lildreth [51] 11nt.C1..... .JHtMd l/lfl v[57] ABSTRACT [58] Field offiearcllt ..8/30.1,D1G. 1; 117/161 ZA,

1 17/1333 p 47 424/133; 3/1 Plastics are rendered nonthrombogenic byhepanmzmg them M. following a treatment with an amino alkyl tri alkoxysilarie in an inert solvent. The solvent is preferably one capable ofRefiemmes Cited swelling the plastic. 1n the treatment of fluorocarbonplastics, a preliminary treatment with sodium is employed. The aminoUNITED STATES PATENTS groups which become attached to the plastic arethus caused 3,512,915 5/1970 Speier ..S/8 to bond heparin to the surfaceeffectively to impart anticoagulating properties.

3,475,410 10/1969 Britton.. .....424/l83X 2 Claims, N0 DrawingsHEPARINIZATION 01F PLASTllC This invention is directed to the productionof plastics having nonthrombogenic surface characteristics. Plastics ofthis type are in demand for use in prosthetic and therapeutic apparatusfor handling blood under conditions where clotting would tend to occur.

When blood is brought into contact with plastics, glass or other strangesurfaces, it tends to clot in a relatively short time unless precautionshave been taken to prevent this. One common precaution currently underconsiderable investigation is the treatment of the surface with heparin,a substance known to have anticoagulant properties when in contact withblood. The presence of heparin on the surface imparts nonthrombogeniccharacteristics.

1 have developed a new and improved method of treating numerous plasticsto bond heparin to their surfaces in a very simple and effective manner.In particular my method provides a nonthrombogenic surface in a mannerthat does not in other ways adversely affect the blood as by increasinghemolysis as will happen in other known methods.

In carrying out my method I make use of the fact that heparin insolution will combine with primary amino groups and form a remarkablystable bond. In this connection it will be noted that heparin isgenerally considered to be a highmolecular weight (e.g., 16,000)tetrasaccharide which is highly negative on account of sulfate andsulfonate groups capable of bonding with the positive amino groups.

According to this invention the plastic material to be treated iscontacted with a solution of an amino alkyl tri alkoxy silane dissolvedin an organic solvent which is preferably capable of swelling theplastic, and which is also preferably water miscible. After the plastichas been contacted with the silane solution it is removed and treatedwith an aqueous solution of heparin, to hydrolyze the trimethoxy groupand to cause heparin to be bound to the plastic surface.

Plastics thus treated may be placed in contact with blood and will befound to exhibit greatly prolonged clotting times, depending on thenature of the plastic, the nature of the silane, the amount of aminogroups present and the amount of heparin with which it has been causedto react.

My invention is based on the concept of chemically or physically bondingthe silane to the plastic preferably by utilizing a solvent which willswell the plastic, and in so doing carry the silane in solution onto it.Treatmentof the plastic with an aqueous solution causes hydrolysis ofthe alkoxy groups to form hydroxy groups. The latter condense with theelimination of water and form a cross linked polymeric structure whichis attached to the plastic surface and presents primary amino groups towhich the heparin readily bonds.

In the treatment of fluorocarbons such as Teflon it is preferable tocontact the surface first with sodium or similar alkali metal in themanner commonly employed in treatments to render the polymer bondable toother materials. This treatment consists generally in a surfaceapplication to the plastic of an activated sodium solution which isactually a colloidal dispersion of sodium in a hydrocarbon. Theso-called activated sodium solutions are commercially available undersuch trademarks as Fluoroetch Safety Solvent and Tetraetch" for thepurpose of rendering the fluorocarbon plastic bondable by means ofadhesive cements.

The sodium treatment serves to modify the surface of the fluorocarbon bycausing the formation of a carbonaceous film, and by forming reactiveradicals on the plastic surface in place of fluorine atoms. The surfaceis thus made compatible with the silane, and reactive with the hydroxygroups which effect the actual bonding of the amino groups to thesurface.

The following examples set forth representative methods for practicingofthis invention.

In each case the plastic was immersed in the silane solution for 2 Vahours, then washed in pure solvent and immersed in a heparin solutioncontaining 100 mg. heparin dissolved in a mixture of 7 ml. of distilledwater and ml. of methanol for 22 hours. The heparinized plastic was nextdried at 50 C. for 3 hours, immersed for 220 hours in distilled water(which was changed 3-4 times per day) flushed with saline solution andfilled with fresh bovine blood.

EXAMPLE l Plastic Silicone rubber tubing 3.5 mm. ll) X 4.5 mm. OD

X 60 cm. long 4 grams of N (trimethnxy silyl propyl) ethylene diamine(Dow Corning 7. 6020) in 20 ml.

tetrahydrofurane Over 13 days Treating Solution Clotting lime EXAMPLE llSolution Clotting time EXAMPLE [ll Plastic Solution Polyvinyl chloride 4g. of Z 6020 in 20 ml. acetone also known as N-Baminoethyl-a-aminopropyltrimcthoxy silane EXAMPLE IV Plastic Polyurethane Solution 4 g. of Z6020 in 20 ml.

methylethylketone Although this invention has been described withreference to specific plastics, solvents and silanes it is contemplatedthat obvious modifications will readily occur to those skilled ingeneral, the process may be practiced with other organic polymers bytreatment with a silane dissolved in a solvent. Those skilled in the artare well familiar with these techniques concerning the effects ofsolvent-type liquids on organic polymers. Water miscible solvents arepreferred, but ones not of themselves water miscible may be used, eithermixed with water miscible solvents, or in a step followed by applicationof an intermediate solvent with which both it and water are miscible.

At present the preferred silane has been Dow Z 6020, but it iscontemplated that others of the general formula R, is organic structureR is lower alkyl or phenyl would be equally effective. It is known thatthe OR; groups readily hydrolyze to OH groups which will react in themanner described, and that Nl-l groups readily bond with heparin. it isaccordingly believed evident that numerous compounds of this type aresuitable. in particular 'y-aminopropyl triethoxy silane also astrimethoxy silane N- (dimethoxy methyl silyl isobutyl)-ethylene diamineBis (B- hydroxyethyl )y-aminopropyl triethoxy silane Having thusdisclosed my invention and described in detail a preferred embodimentthereof] claim and desire to secure by Letters Patent:

l. The method of treating a fluorocarbon plastic to impart heparin tocause hydrolysis of said silane and bonding thereto nonthrombogenicproperties which comprises first contacting of heparin. said plasticwith sodium, thereafter contacting said plastic The method defined yclaim 1 wherein the Silanfi l (Ci-1 Si (CH NH (CI-[ h NH with an aminoalkyl tri alkoxy silane solution in an organic solvent and thereaftercontacting said plastic with water and 5 v UNITED STATES PATENT OFFICECERTIFICATE OF COREUMON fiatem 3,639,141 Dated February 1; 1972xnrentfls) Manfred F. Dyck It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 4, line 4, Claim 2, "(CI-1 shnuld readq m m igned and sealed this18th day of July 1972.

(SEAL) Attest:

EDJARD M..?'LETCHER, JR. ROBERT GOTTSCHALK Attesting Officer-Commissioner of Patents

2. The method defined by claim 1 wherein the silane is (CH3)3 Si (CH2)3NH (CH2)2 NH2.